Process for preparation of 4,5-Epoxymorphinan-6-oxyglucuronides

ABSTRACT

Conjugation of 4,5-Epoxymorphinan-6-ols with Bromoglucuronides in the presence of Zinc containing compounds as activator under conditions capable of forming 4,5-Epoxymorphinan-6-oxyglucuronides is disclosed. This novel approach provides an efficient method for preparation of both anomers of 4,5-Epoxymorphinan-6-oxyglucuronides. The deprotected end products are useful as analgesic agents.

BACKGROUND OF THE INVENTION

[0001] According to recent publications the morphine metaboliteMorphine-6-β-D-glucuronide (M6G) [6] is a more effective and longerlasting analgesic drug than Morphine [5] with fewer side effects¹ and,therefore, there is much interest in using M6G, rather than Morphine, asa pain killing drug.²

[0002] The traditional approach to glycosylation of4,5-Epoxymorphinan-6-ols explores Bromoolucuronides as glycoside donorand the Koenings-Knorr procedure for the activation of Bromoglucuronides(Berrang, B., et al., Synthesis, 1997, p. 1165 and references citedtherein).

[0003] Another approach (Scheinmann, F. et. al., U.S. Pat. No.5,621,087, see claim 1, 2, 5 and 6, abstract, examples, column 4, line25-line 45) explores the use of Lewis acids (of the type BF₃ and TMSOTf)rather than heavy metals based Lewis acids (March, J., “Advanced OrganicChemistry”, 4-th edition, A Whiley-Interscience publicaiton, pp. 260-3)for the activation of Bromoglucuronides.

[0004] Unfortunately, we did not succeed to obtain4,5-Epoxymorphinan-6-oxyglucuronide from Bromoglucuronides usingactivators proposed in U.S. Pat. No. 5,621,087 and did not find suchexamples in the literature.

[0005] Unexpectedly we found that the O-clycosylation of4,5-Epoxymorphinan-6-ols with Bromoglucuronides was accelerated by Zinccontaining compounds to give 4,5-Epoxymorphinan-6-oxyglucuronides offormula [1] with high yield.

[0006] wherein:

[0007] position 7 and 8 can be olefin as shown or dihydro adduct;

[0008] R¹ are alkyl, haloalkyl, arylmethyl, acyl, alkoxycarbonyl,

[0009] aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl orallyloxycarbonyl,

[0010] R² is alkyl, haloalkyl or aralkyl;

[0011] R³ is alkyl, arylmethyl, allyl, cyclopropylmethyl,cyclobutylmethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl,haloalkoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl or hydrogen;

[0012] R⁴ is alkyl, haloalkyl, arylmethyl, 2-(4-morpholinyl)ethyl, acyl,alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonylor allyloxycarbonyl.

[0013] We also found that the α and β anomeric selectivity of theconjugation product can be controlled by using different O-protectinggroups in aglycon and in Bromoglucuronide as well as by varying theratio between 4,5-Epoxymorphinan-6-ols and Zinc containing compounds.

[0014] It is important to note that only the H-anomer of4,5-Epoxymorphinan-6-oxyglucuronides was obtained according toKoenings-Knorr procedure and U.S. Pat. No. 5,621,077 procedure (but withanother then Bromoglucuronide glycoside donor).

[0015] All of the previously disclosed methods have serious drawbacksfor producing material to be used as a pharmaceutical drug. A desirablegoal, met by the present invention, has been to devise a syntheticprocedure without using commercially inaccessible and expensivereagents, and which cleanly produces the desired4,5-Epoxymorphinan-6-oxyglucuronides, avoiding tedious and expensivepurification steps.

SUMMARY OF THE INVENTION

[0016] The present invention provides a commercially acceptable processfor conjugation of 4,5-Epoxymorphinan-6-ols of formula [3] withBromoglucuronides of formula [2] in the presence of Zinc containingcompounds under conditions capable of forming4,5-Epoxymorphinan-6-oxyglucuronides [1].

[0017] wherein

[0018] position 7 and 8 can be olefin as shown or dihydro adduct;

[0019] R¹, R², R³, and R⁴, are as defined above.

[0020] This novel approach was used for the preparation of the knownanalgesic agent Morphine-6-β-glucuronide [4] and of its α-anomer.

[0021] Other features and advantages will be apparent from thespecification and claims.

DETAILED DESCRIPTION OF THE INVENTION

[0022] The present invention is related to a novel process forconjugation of 4,5-Epoxymorphinan-6-ols with Bromoglucuronides.

[0023] Particularly, the present invention relates to the use of Zinccontaining compounds for the activation of Bromoglucuronides in theO-glycosylation reaction of 4,5-Epoxymorphinan-6-ols.

[0024] This novel approach has the following advantages:

[0025] Zinc containing compounds as activating reagents ofBromoglucuronides are inexpensive and commercially available.

[0026] Use of different O-protecting groups in the aglycon and in theBromoglucuronide as well as different ratio of 4,5-Epoxymorphinan-6-olsand Zinc containing compounds enable to obtain high anomeric selectivityand produce at will with a high degree of preference either the α or theβ anomer.

[0027] Although any 4,5-Epoxymorphinan-6-ols are suitable for thisO-glycosylation, preferably, compounds of formula [3] are used

[0028] wherein

[0029] position 7 and 8 can be olefin as shown or dihydro adduct; R³ andR⁴ are as previously defined.

[0030] More preferably, said 4,5-Epoxymorphinan-6-ols are selected from3-O-Acylmorphine, 3-O-Acylnormorphine, 3-O-Acylnalbuphine,3-O-Acylnalorphine, 3-O-Acyldihydromorphine, 3-O-Benzylmorphine,3-O-Benzyldihydromorphine, N,O³-Dibenzylnornorphine, Codeine,Ethylmorphine, Dihydrocodeine, Pholcodine, 3-O-Alkoxycarbonylmorphine,3-O-Benzyloxycarbonylmorphine, N,O³-Bis(benzyloxycarbonyl)normoiphine.

[0031] Although any Bromoglucuronide may be used, it is preferred thatcompounds of formula [2] are used.

[0032] wherein

[0033] R¹ and R² are as previously defined.

[0034] More preferably the Bromoglucuronides of the present inventionare selected from the compounds of formula [2a].

[0035] wherein

[0036] R are acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl,

[0037] vinyloxycarbonyl, allyloxycarbonyl;

[0038] R² is as previously defined.

[0039] Most preferably Bromoglucuronides of formula [2b] are used.

[0040] wherein

[0041] R are as previously defined.

[0042] Although any Zinc containing compound suitable as activatingreagents for this O-glycosylation can be used, preferably, Zinc Bromideis used.

[0043] It is preferred that about 0.01 equivalents to about 4equivalents and especially preferred that about 0.5 equivalents to about2 equivalents of Zinc containing compound is used.

[0044] Preferably about 1 equivalent to about 2 equivalents of theBromoglucuronide [2] is used. It is specially preferred that about 1equivalent to about 1.5 equivalents of Bromoglucuronide [2] is used. Thesaid 4,5-Epoxymorphinan-6-ol [31] may be used as an individual compoundor alternatively as corresponding salts thereof or complexes. Especiallypreferred is the use of said Zinc containing salt or complexes of [3]without using additional Zinc containing compounds as promoter for saidcoupling. It is preferred that the said complexes may be prepared insitu.

[0045] It may be also preferred to conduct the said Zinc activatedO-glycosylation in the presence of additives to buffer or to promote thesaid Zinc containing compounds. The above additives may be selected frommolecular sieves, tertiary amines, tetraalkylureas, organic andinorganic acids and salts.

[0046] Any reaction-inert solvent may be used. As used above andelsewhere herein, the expression “reaction-inert solvent” refers to asolvent which does not react or decompose with starting materials,reagents, intermediates or products in a manner which adversely affectsthe yield of the desired product. In general, the solvent can comprise asingle entity, or contain multiple components. Preferably the sovent isa non-protic reaction inert solvent and it is especially preferred thatthe solvent is Dichloromethane because of the exellent stereoselectivityit provides. Another solvent may be Chloroform or Dichloroethane.

[0047] Any environment or conditions (e.g. temperature, time, solvent)suitable for (i.e., capable of) forming the desired4,5-Epoxymorphinane-6-oxyglucuronides may be used. However, it ispreferred that the reaction occurs at a temperature of about −20° C. toabout 100° C. and preferably from about 40° C. to 65° C. Below about−20° C. the reaction can be slow and above about 100° C. undesired sidereactions (e.g. anomerisation) can occur. This reaction is convenientlycarried out at about 0.5 to about 3 atmospheres, however, the highpressures are espesially preferred for the said coupling.

[0048] The present invention could be used as a general method toproduce a large number of new compounds. As a result of the saidcoupling also the salts and complexes of4,5-epoxymorphinan-6-oxyglucuronides [1] could be obtained in aconvenient way.

[0049] This invention makes a significant advance in the field of4,5-Epoxymorphinan-6-oxyglucosides by providing efficient methods ofpreparing both anomers of 4,5-Epoxymorphinan-6-oxyglucuronides. Thedeprotected end products are usefuil as analgesic agents.

[0050] It should be understood that the invention is not limited to theparticular embodiments shown and described herein, but that variouschanges and modifications may be made without departing from the spiritand scope of this novel concept as defined by the following claims.

EXAMPLES Example 1 Preparation of Codeine-β-glucuronide [4a]

[0051]

[0052] 1.1 Preparation of Methyl(3-O-methylmorphin-6-yl-2′,3′,4′-tri-O-acetyl-β-D-glucopyranosid)uronate[1e]

[0053] A mixture of Methyl acetobromo-α-D-glucuronate [2c] (0.20 g),Codeine [3b] (0.10 g), 3 Å Molecular Sieves (0.3 g) and Dichloromethane(10 mL) was stirred at room temperature for 5 hours. Anhydrous ZincBromide (0.08 g) was added in one portion and the resulting mixture wasrefluxed for 48 hours. Dichloromethane (20 mL) and SodiumHydrogencarbonate saturated aqueous solution (10 mL) were added to thecooled reaction mixture. After stirring for 30 min the organic layer wasseparated and washed with Sodium Hydrogencarbonate saturated aqueoussolution and Water. The aqueous layers were combined and washed withDichloromethane (20 mL) The combined organic layers were dried overanhydrous Sodium Sulfate, filtered and evaporated under reducedpressure. After purification of the residue the desired product wasobtained in the yield of 58% (0.12 g). Its structure was confirmed by ¹HNMR (CDCl)₃

[0054] 1.2 Hydrolysis of compound [1e].

[0055] Hydrolysis of compound [1e] was carried out according to theknown procedure (Carrupt, P.-A. et al., J. Med. Chem., 1991, v. 34,1272). Codeine-β-glucuronide was obtained with 50% yield. Its structurewas confirmed by ¹H NMR (D2O), ¹³C NMR, HR-MS.

EXAMPLE 2 Preparation of Morphine-6-β-glucuronide [M6G] [4].

[0056]

[0057] 2.1 Preparation of Methyl (3-O-methoxycarbonylmorphin-6-yl-2′,3′,4′-tri-O-acetyl-β-D-glucopyranosid)uronate [1f]

[0058] A mixture of Methyl acetobromo-α-D-glucuronate [2c], (39.7 g, 100mmol), 3-O-Methoxycarbonylmorphine [3c] (22.8 g,66.5 mmol) 3 Å MolecularSieves (50.0 g) and Chloroform (300 mL) was stirred at room temperaturefor 1 hour. Anhydrous Zinc Bromide (16.1 g, 71.4 mmol) was added in oneportion and the resulting mixture was stirred at 50-55° C. for 60 hoursunder Argon. Sodium Hydrogencarbonate saturated aqueous solution (200mL) was added to the cooled to room temperature reaction mixture and thestirring was continued for additional 30 min. The organic layer wasseparated, washed with water, dried over anhydrous Sodium Sulfate,filtered through a short Silica gel column and evaporated under reducedpressure to give 35.0 g (80%) of the crude product. Afterrecrystallisation from iso-Propanol 20.3 g (46.4% yield) of Methyl(3-O-methoxycarbonylmorphin-6-yl-2′,3′,4′-tri-O-acetyl-β-D-glucopyranosid)uronate [1f] was obtained. Itsstructure was confirmed by ¹H NMR (CDCl₃).

[0059] 2.2. Hydrolysis of compound [1f]

[0060] Hydrolysis of compound [1f] was carried out according to knownprocedure (Carrupt, P.-A. et al., J. Med. Chem., 1991, v. 34, 1272) andgave M6G [4] with 56% yield. Its structure was confirmed by ¹H NMR(D2O), ¹³C NMR.

EXAMPLE 3 Preparation of Morphine-6-α-glucuronide [4b].

[0061]

[0062] 3.1 Preparation of Methyl(3-O-acetylmorphin-6-yl-2′,3′,4′-tri-O-acetyl-α/β-D-glucopyranosid)uronate [1g]

[0063] A mixture of Methyl acetobromo-α-D-glucuronate [2c] (6.0 g, 15mmol), 3-O-Acetylmorphine [3c] (3.23 g, 10 mmol) and 3 Å MolecularSieves (9.0 g) and Dichloromethane (50 mL) was stirred at roomtemperature for 5 hours. Anhydrous Zinc Bromide (4.50 g, 20 mmol) wasadded in one portion and the resulting mixture was refluxed for 48hours. Solution of Sodium hydrogencarbonate (8.0 g) in 80 mL water andDichloromethane (80 mL) were added to the cold solution. After stirringfor 30 min the organic layer was separated and the aqueous layer waswashed with Dichloromethane. The combined organic solution was washedwith water, dried over anhydrous Sodium Sulfate, filtered and evaporatedunder reduced pressure. The residue was purified on a short Silica gelcolumn (Dichloromethane →Dichloromethane/Methanol 30:1 v/v) and afterconcentration under reduced pressure 5.7 g of yellowish powder of thedesiredMethyl(3-O-acetylmorphin-6-yl-2′,3′,4′-tri-O-acetyl-D-glucopyranosid)uronate[1g] (α/β6:1 mixture according to ¹H NMR spectra) (91% yield) wasobtained.

[0064] 3.2 Hydrolysis of compound [1g].

[0065] Sodium Hydroxide (0.40 g, 10.0 mmol) solution in 7.5 mL water wasadded to a stirred solution of Methyl(3-O-acetylmorphin-6-yl-2′,3′,4′-Tri-O-acetyl-α/β-D-glucopyranosid)uronate(1.6 g, 2.0 mmol) in 30 mL Methanol and the mixture was stirredovernight at room temperature. The solution was then acidified withglacial Acetic acid (5.25 g, 87.3 mmol) to pH 5.5. The solution wascooled to 0° C., Ethanol (20 mL) was added and the obtained mixture wasstirred for 1.5 hours. The white precipitate formed under theseconditions was filtered off and washed with Ethanol (2 mL). After dryingunder reduced pressure at 80° C. 0.63 g (62% yield) ofMorphine-6-α-glucuronide [4b] was obtained. Its structure was confirmedby ¹H NMR (D₂O), ¹³C NMR, HR-MS.

EXAMPLE 4-20 Preparation of Compound of Formula [1b]

[0066] The syntheses are described by the following Scheme. Theprocedures set forth in Example 3 were followed with the exceptionsapparent from Table 1. Ratio β/α was determined according to ¹H NMRand/or HPLC.

[0067] The procedures set forth in Example 3 were followed with theexceptions apparent from Table 1. Ratio β/α was determined according to¹H NMR and/or HPLC. TABLE 1 ZnBr₂/ Ex. No. R⁴ R [3a] Solv. β/α 4 Ac Ac0.8 CH₂Cl₂ 10:1  5 Ac Ac 0.9 CH₂Cl₂ 6:1 6 Ac Ac 1.0 CH₂Cl₂ 2:1 7 Ac Ac1.2 CH₂Cl₂ 1:2 8 Ac Ac 1.5 CH₂Cl₂ 1:4 9 Ac Ac >1.5 CH₂Cl₂ 1:6 10 Ac i-Bu0.90 CH₂Cl₂ 2:1 11 Ac i-Bu 1.2 CH₂Cl₂ 1:1 12 i-Bu i-Bu 0.85 CH₂Cl₂3.5:1   13 i-Bu i-Bu 1.0 CH₂Cl₂ 2:1 14 Bz Ac 1.0 CH₂Cl₂ 2:1 15 Bz i-Bu0.9 CH₂Cl₂ 29:1  16 Bz i-Bu 1.5 CH₂Cl₂ 6:1 17 Bz Bz 1.0 CH₂Cl₂ 10:1  18MeOCO Ac 1.0 CHCl₃ 6:1 19 MeOCO Ac 1.4 CH₂Cl₂ 5:1 20 Me Ac 1.1 CH₂Cl₂>99:1   

EXAMPLE 21 Preparation of Methyl (3-O-Acetylmorpbin-6-yl-2′,3′,4′-Tri-O-acetyl-β-D-glucopyranosid)uronate of formula [8]

[0068]

[0069] A suspension of 6.00 g of MethylTri-O-acetyl-1-α-bromo-1-deoxy-D-glucopyranuronate of formula [9], 3.23g of freshly prepared, vacuum-dried 3-O-Acetylmorphine⁶ and 9.00 g of 3Å Molecular Sieves in CH₂Cl₂ was stirred at room temperature for 5hours. Anhydrous Zinc Bromide, 2.20 g was added in one portion and theresulting mixture was refluxed for 24 hours. Then an additional 0.30 gof anhydrous Zinc Bromide was added and the mixture was refluxed foradditional 24 hours. After this period, the red solution was cooled toroom temperature and the mixture of Methylene Chloride (150 mL) andSodium Hydrogen carbonate saturated aqueous solution (80 mL) was addedto the reaction mixture. After stirring for 30 min. the organic layerwas separated and washed consequently with Sodium Hydrogen carbonatesaturated aqueous solution and Water. The combined aqueous layers werewashed with Methylene Chloride. The combined organic layers were driedover Sodium Sulphate anhydrous, filtered and evaporated under reducedpressure. After purification of the residue the desired product wasobtained in the yield of 91% (5.7 g).

REFERENCES

[0070] 1. Osborne, R., et al., Br. J. Clin. Pharm. 1992, v. 34, 130

[0071] 2. Frances, B., et al., J. Pharm. Exp. Ther., 1992, v. 262, 25

1. A process for the synthesis of a protected4,5-Epoxymorphinan-6-oxyglucuronide of formula [1] or a salt or complexthereof

wherein: position 7 and 8 are olefin as shown or dihydro adduct; R¹ isalkyl, hialoalkyl, arylmnethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl,lialoalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl, R² is alkyl,haloalkyl or aralkyl; R³ is alkyl, arylmethyl, allyl, cyclopropylmethyl,cyclobutylmethyl, hydrogen, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalko xycarbonyl , vinyl oxycarbonyl or all yl oxycarbonyl ; R⁴ is alkyl,haloalkyl, arylmethyl, 2(4-morpholinyl)ethyl, acyl, alkoxycarbonyl,aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl orallyloxycarbonyl. comprising reaction of a Bromoglucuronide of theformula [2]

wherein R¹ and R² are as previously defined; with a4,5-Epoxymoiphinan-6-ols of the formula [3] or a salt or complex thereof

wherein R³ and R⁴ are as previously defined; in the presence of a Zinccontaining compound under conditions capable of forming said protected4,5-Epoxymoiphinan-6-oxyglucuronide [1] or a salt or complex thereof. 2.A process according to claim 1 wherein said 4,5-Epoxymorphinan-6-ol isselected from the compounds of the formula [3a]

wherein R⁴ is as previously defined.
 3. A process according to claim 1wherein said 4,5-Epoxymorphinan-6-ol is selected from 3-O-Acylmorphine,3-O-Acylnormorphine, 3-O-Acylnalbuphine, 3-O-Acylnalorphine,3-O-Acyldihydromorphine, 3-O-Benzylmorphine, 3-O-Benzyldihydromorphine,N,O³-Dibenzylnormorphine, Codeine, Ethylmorphine, Dihydrocodeine,Pholcodine, 3-O-Alkoxycarbonylmorphine, 3-O-Benzyloxycarbonylmorphine,N,O³-Bis(benzyl oxycarbonyl)normorphine.
 4. A process according to claim1 wherein said Bromoglucuronide is selected from compounds of formula[2a]

wherein R is acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl,vinyloxycarbonyl or allyloxycarbonyl; R² is as previously defined.
 5. Aprocess according to claim 1 wherein said Bromoglucuronide is selectedfrom compounds of formula [2b]

wherein R is as previously defined.
 6. A process as recited in claim 1wherein said protected 4,5-Epoxymorphinan-6-oxyglucuronide is anN-Methyl-4,5-epoxymorphinan-6-oxyglucuronide of formula [1a] orderivative.

wherein: position 7 and 8 can be olefin as shown or dihydro adduct; R isacyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl,vinyloxycarbonyl, allyloxycarbonyl, benzyoxylcarbonyl,nitrobenzyloxycarbonyl, methoxybenzylcarbonyl or aroxycarbonyl R2 isalkyl, haloalkyl or aralkyl; R⁴ is alkil, haloalkyl, arylmethyl,2-(4-morpholinyl)ethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl,haloalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl.
 7. A processas recited in claim 1 wherein R² and R³ are methyl.
 8. A processaccording to claim 1 wherein said protected4,5-epoxymorphinan-6-oxyglucuronide is of formula [1b].

wherein R and R⁴ are as previously defined.
 9. A process as recited inclaim 1 wherein the said reaction occurs in the presence of molecularsieves.
 10. A process as recited in claim 1 wherein the reaction occursin a non-protic reaction inert solvent.
 11. A process as recited inclaim 10 wherein the inert solvent is selected from Chloroform,Dichloromethane or Dichloroethane.
 12. A process as recited in claim 1wherein the Zinc containing compound is Zinc Bromide.
 13. Use of a Zinccomplex of a general formula [3b]

wherein R³ and R⁴ are as previously defined; X is a halogen or acyano-group; n 0.5÷2 for preparation of a protected4,5-Epoxymorphinan-6-oxyglucuronide of a general formula [1] or a saltor complex thereof

wherein R¹, R², R³ and R⁴ are as previously defined.
 14. A process forthe synthesis of a protected 4,5-Epoxymorphinan-6-oxyglucuronide offormula [1] or a salt or complex thereof

wherein: position 7 and 8 are olefin as shown or dihydro adduct; R¹ isalkyl, haloalkyl, arylmethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl,haloalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl; R² is alkyl,haloalkyl or aralkyl; R³ is alkyl, arylmethyl, allyl, cyclopropylmethyl,cyclobutylmethyl, hydrogen, acyl, alkoxycarbonyl, aralkoxycarbonyl,haloalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl; R⁴ is alkyl,haloalkyl, arylmethyl, 2-(4-morpholinyl)ethyl, acyl, alkoxycarbonyl,aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl orallyloxycarbonyl comprising reaction of Bromoglucuronide of the formula[2]

wherein R¹ and R² are as previously defined; with complex of the formula[3b] under conditions capable of forming said protected4,5-Epoxymorphinan-6-oxyglucuronide [1] or a salt or complex thereof.15. A compound having the following formula:

wherein: position 7 and 8 is olefin as shown or dihydro adduct; R² andR³ are as previously defined; R⁶ is selected from alkoxycarbonyl,aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyland R⁵ is selected from alkyl, haloalkyl, arylmethyl, acyl,alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl,allyloxycarbonyl or R⁶ is selected from alkyl, haloalkyl, arylmethyl,2-(4-morpholinyl)ethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl,haloalkoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl when one of R⁵ isselected from alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl,vinyloxycarbonyl, allyloxycarbonyl.
 16. A compound having the followingformula:

wherein: position 7 and 8 is olefin as shown or dihydro adduct; R⁷ ishydrogen, alkyl, haloalkyl, arylmethyl, acyl, alkoxycarbonyl,aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl orallyloxycarbonyl; R⁸ is hydrogen, alkyl, haloalkyl or aralkyl; R⁹ ishydrogen, alkyl, arylmethyl, allyl, cyclopropylmethyl, cyclobutylmethyl,hydrogen, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl,vinyloxycarbonyl or allyloxycarbonyl; R¹⁰ is hydrogen, alkyl, haloalkyl,arylmethyl, 2-(4-morpholinyl)ethyl, acyl, alkoxycarbonyl,aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl orallyloxycarbonyl.
 17. A compound of formula [1c] according to claim 15wherein R² and R³ are both Me.
 18. A protected4,5-Epoxymorphinan-6-oxyglucuronide synthesised according to any ofclaims 1 to 12 or
 14. 19. A process for synthesising M6G comprising:synthesising a protected 4,5-Epoxymorphinan-6-oxyglucuronide accordingto any of claims 1 to 12 or 14; and hydrolysing the protected4,5-Epoxymorphinan-6-oxyglucuronide to form M6G.
 20. M6G synthesisedaccording to claim
 19. 21. M6G synthesised using a zinc complexaccording to claim 13.